According to published statistics, over 40 million people are estimated to be infected with Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) worldwide and approximately 22 million people have died from AIDS (CDC, 2000 international Statistics). To combat this epidemic, exhaustive research has focused on either inhibiting the molecular mechanisms of this virus or treating the symptoms associated with it.
While AZT was the pioneer drug first prescribed for this malady, numerous drugs such as protease inhibitors, additional nucleoside analogue transcriptase inhibitors, or non-nucleoside reverse transcriptase inhibitors have become available in recent years. Because of their improved effectiveness, these drugs mark great strides in treating HIV and AIDS. Even though these drugs have shown promise in controlling viral infection, reservoirs of infected cells remain and possibly give rise to resistant variants. For example, many of these drugs do not cross the blood/brain barrier efficiently, which allows for unchecked replication and transmission throughout the following cells in the brain: capillary endothelial cells, astrocytes, macrophages (microglia), oligodendrocytes, choroid plexus, ganglion cells, neuroblastoma cells, glioma cells, and neurons. The consequences of CNS infection include neurologic and psychiatric complications such as dementia, cognitive disorders, major depression, psychosis, and polyneuropathies.
In addition to the drugs mentioned above, much research has focused on the inhibition of HIV integrase (IN), an enzyme that facilitates HIV DNA integration into the genome. However, because in vitro reactions occur in an aggregated rather than a soluble system, IN has proven rather problematic to study. It is theorized that within a cell IN performs (1) a 3′-end processing step of HIV DNA in which two nucleotides are cleaved from the 3′ end of the viral DNA and (2) strand transfer reaction in which the 3′ ends of the viral DNA are ligated to the target DNA. To function properly, it is believed that IN must assemble into a complex with viral DNA, host DNA, and additional viral and host protein factors. To date, numerous strand transfer inhibitors of IN have been found which include raltegravir (also known as Isentress or MK 0518), diketo analogues such as S-1360, L-870, 810, and GS-9137, and naphthyridione GSK 36473 (Philippe Cotelle, Recent Patents on Anti-Infective Drug Discovery, 1:1-15 (2006)). However, due to IN mutations, HIV may become resistant to these drugs thus resulting in high failure rates and inefficient treatment.
While drugs for treating HIV and AIDS have been identified, there is a need for novel drugs that inhibit HIV integrase and for drug-screening methods that rapidly allow for the screening of peptides or small molecules that interact with and either inhibit or reduce IN activity.